JULIE M. VOSE. 3. Identify future directions for radioimmunotherapy in cancer medicine.

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1 The Oncologist Lymphoma Bexxar : Novel Radioimmunotherapy for the Treatment of Low-Grade and Transformed Low-Grade Non-Hodgkin s Lymphoma JULIE M. VOSE Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA Key Words. Radioimmunotherapy Immunotherapy Tositumomab Non-Hodgkin s lymphoma Rituximab-refractory LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe advances in clinical radioimmunotherapy. 2. Discuss ongoing translational research in radioimmunotherapy. 3. Identify future directions for radioimmunotherapy in cancer medicine. CME Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Purpose. Immunotherapy using monoclonal antibodies to specifically target B cells has provided new hope to many patients with indolent lymphomas, particularly those with chemotherapy-refractory disease. Lymphomas are extremely sensitive to radiation, and significant progress has been made over the last decade in the development of radioimmunotherapy with anti-cd20 antibodies. Materials and Methods. Herein we review clinical experience with tositumomab and iodine I 131 tositumomab (Bexxar ; Corixa Corporation; South San Francisco, CA; and GlaxoSmithKline; Philadelphia, PA) in patients with non-hodgkin s lymphoma. Results. Therapy with Bexxar has demonstrated high response rates and long durations of response compared with unconjugated anti-cd20 antibodies in patients with relapsed low-grade and transformed low-grade non-hodgkin s lymphomas. Iodine-131 (I- 131) has a long history of clinical experience, an excellent safety record, and favorable nuclear and pharmacologic properties. Importantly, the gamma emissions of iodine-131 facilitate accurate dosimetry to calculate the appropriate patient-specific therapeutic activity to deliver a predetermined total-body dose of radiation, thereby minimizing hematologic toxicity. In clinical trials of Bexxar, objective response rates ranged from 54%-71% in heavily pretreated patients. In the pivotal trial, the number of patients with a longer duration of response after treatment with Bexxar was significantly greater than the number of patients with a longer duration of response after their last qualifying chemotherapy regimen. In 76 newly diagnosed patients, the objective response rate was 97%, and 63% of patients achieved complete responses. Conclusion. These data suggest that Bexxar will become an important new option in the treatment of indolent lymphoma. The Oncologist 2004;9: Correspondence: Julie M. Vose, M.D., Department of Internal Medicine, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska, , USA. Telephone: ; Fax: ; jmvose@unmc.edu Received February 21, 2003; accepted for publication February 11, AlphaMed Press /2004/$12.00/0 The Oncologist 2004;9:

2 161 Bexxar for NHL INTRODUCTION Recent developments in the use of monoclonal antibodies to target malignant B cells have produced promising results in the treatment of low-grade (i.e., indolent) non- Hodgkin s lymphoma (NHL). Investigators have taken advantage of the well-defined surface antigens on differentiated B cells, including CD20 [1], CD19 [2], CD22 [3], CD52 [4], and HLA-DR [5, 6], and have targeted these antigens with a variety of monoclonal antibodies. CD20 is an excellent target for immunotherapy because it is not shed from the cell surface or internalized when bound by antibody, and it is expressed by nearly all B-cell tumors. When anti-cd20 antibodies bind to surface antigens, they induce apoptosis, antibody-dependent cellular cytotoxicity, and complement-dependent cellular cytotoxicity of lymphoma cells [7-10]. Early studies with the chimeric anti-cd20 monoclonal antibody rituximab produced favorable results in patients with relapsed, low-grade NHL. In the pivotal rituximab trial with 166 patients, rituximab induced a 48% objective response (OR) rate, including a 6% complete response (CR) rate, and the median time to progression for responders was 13 months [1]. Although that study established the efficacy of monoclonal antibody therapy in relapsed patients, the low CR rate suggested that there was need for other therapeutic advances. Therefore, studies combining chemotherapy with rituximab or utilizing radioimmunotherapy (RIT) with radionuclide-conjugated monoclonal antibodies have been pursued. The combination of rituximab with conventional CHOP chemotherapy has demonstrated both safety and efficacy in patients with untreated or relapsed low-grade NHL [11]. Recently, RIT has been investigated and has demonstrated higher response rates than those achieved with unconjugated antibodies [1, 12-15]. A variety of radioimmunoconjugates has been investigated in patients with low-grade lymphoma [16], including tositumomab and iodine I 131 tositumomab (Bexxar ; Corixa Corporation; South San Francisco, CA; and GlaxoSmithKline; Philadelphia, PA; and yttrium-90 (Y-90)-labeled Y2B8 (ibritumomab tiuxetan, Zevalin ; IDEC Pharmaceuticals Corporation; San Diego, CA; The safety and efficacy of therapy with Bexxar were first established in the initial phase I/II study conducted at the University of Michigan, which demonstrated ORs in 71% of patients with relapsed low-grade and transformed lowgrade NHL, including CRs in 34% of patients [14]. The efficacy of Bexxar was subsequently confirmed in two multicenter trials in relapsed and refractory patient populations and in a single-center study in newly diagnosed patients. The efficacy and safety of Bexxar in patients with lowgrade and transformed low-grade NHL are reviewed based on the cumulative clinical experience over the past 10 years. PHARMACOLOGY Mechanism of Action Radioimmunotherapy is a particularly attractive approach for the treatment of NHL for a variety of reasons. First, lymphomas are among the most radiosensitive of all malignancies [17, 18]. Second, unlike total body irradiation, RIT deposits the greatest energy within the tumor, thereby limiting damage to normal tissues. Third, radiolabeled anti-cd20 antibodies have multiple mechanisms of action. In addition to inducing apoptosis and mediating antibody-dependent cellular cytotoxicity and complement-dependent cellular cytotoxicity, radiolabeled antibodies deliver cytotoxic ionizing radiation. Therefore, unlike unconjugated antibodies, radioimmunoconjugates can be effective when the host immune system is not fully functional, can destroy antigen-negative cells within tumors, and can overcome poor penetration of the antibody into tumors. The high-energy beta particles emitted by I-131 are cytotoxic over distances of approximately 1-2 mm (the average path length is 0.8 mm and the maximum path length is 2.4 mm) [19, 20], thus permitting eradication of antigennegative tumor cells by crossfire from neighboring antibodycoated cells (Fig. 1) [20]. Figure 1. Radioisotope crossfire. Illustration of high-energy beta particle emissions from I-131- and Y-90-conjugated antibodies traversing several cell diameters and destroying cells that are inaccessible to the antibody. Adapted with permission from Press et al. [20].

3 Vose 162 Clinical Pharmacology The clinical pharmacology of I-131 is well suited to radioimmunotherapy. I-131, which has a long track record of clinical experience and an excellent safety profile in the treatment of thyroid conditions, was the first radioisotope used for RIT because it is readily available and is easily conjugated to antibodies. In addition, I-131 can be used for both imaging and treatment by virtue of the fact that I-131 has dual emissions (both beta and gamma particles). Utilizing the gamma emissions, relatively simple dosimetry can be performed and used to calculate the clearance rate of the radionuclide in an individual patient, thus determining the patient-specific therapeutic dose. The half-life of I-131 (approximately 8 days) is also well suited for RIT [21], because it is similar to the halflife of murine antibodies in humans. Therefore, when I-131- labeled tositumomab is bound to CD20, a stable cell-surface molecule, the tumor receives high doses of radiation over several days. Another advantage of I-131 is the relatively short average path length of the beta emissions (approximately 1 mm), which minimizes collateral damage to healthy tissue surrounding the tumor. As the I-131-conjugated antibody is metabolized, the free I-131 metabolites are released into the bloodstream and are rapidly excreted in the urine [22-24]. Free I-131 in the blood may also be taken up by the thyroid; however, accumulation in the thyroid can be effectively blocked by administering a supersaturated potassium iodine (SSKI) solution to patients before and during treatment, thus limiting potential damage. Nevertheless, thyroid dysfunction has been observed in approximately 5% of patients treated with Bexxar. Y-90-labeled anti-cd20 antibodies have also been used in the treatment of lymphoma. Compared with I-131, Y-90 has a shorter half-life and emits higher energy beta particles with a longer average path length. Other beta-emitting isotopes such as copper-67 (Cu-67) appear promising [25], but their availability is extremely limited. Therefore, in terms of half-life, path length, imaging capabilities, and clinical utility, I-131 may have some advantages over other isotopes. Detailed dosimetry studies conducted at the University of Michigan have also shown that iodine I 131 tositumomab is associated with a favorable tumor-to-normal-organ ratio (Fig. 2). The dose-limiting toxicity of Bexxar therapy, as for all RIT, is hematologic; therefore, the ratio of the absorbed radiation dose to bone marrow versus tumor is critical for determining the therapeutic index. In several phase I and II studies with Bexxar, the absorbed radiation dose to the bone marrow was approximately tenfold lower than the dose to the tumor (Fig. 2). A phase I dose-escalation study determined the maximum tolerated total-body dose (TBD) to be 75 cgy in patients with platelet counts 150,000/mm 3 [26]. At this dose level, the absorbed dose to bone marrow was approximately 100 cgy. The majority of patients treated with 75 cgy had only mild-to-moderate myelosuppression 4-6 weeks after treatment, whereas two of three patients treated with wholebody doses of 85 cgy experienced grades 3 and 4 leukopenia and thrombocytopenia [26]. Efficacy in The Treatment of Low-Grade NHL The therapeutic efficacy of Bexxar was demonstrated in three multicenter trials in patients with relapsed and refractory low-grade and transformed low-grade NHL [12, 27, 28] and in a single-institution study in newly diagnosed patients [13]. In all these trials, treatment with Bexxar produced high overall and CR rates depending on the extent of prior therapy (Fig. 3) [16], and many responses were of long durations. Multicenter Phase II Trial In one of the multicenter phase II trials, 47 patients with histologically confirmed, CD20-positive, low-grade (79%) or transformed low-grade (21%) NHL were treated with Bexxar [27]. The median time from diagnosis to study entry was 41 months; the median patient age was 49 years. All patients had previously been treated with at least one chemotherapy regimen, which contained an anthracycline or anthracenedione, and all had either failed to respond to or had relapsed within 1 year of their last qualifying chemotherapy (LQC). The majority of patients was heavily pretreated, with a median of four (range 1-8) prior chemotherapy regimens. The administered therapeutic activity ranged from mci, to deliver a TBD of 65 or 75 cgy. In that trial, 57% of patients had ORs, with a median duration of 9.9 months, and 32% of patients had CRs, with a Mean dose, cgy 1, RIT-I-000 RIT-II-001 RIT-II-003 Bone marrow Lungs Bladder Kidneys Tumor Figure 2. Organ versus tumor dosimetry. Organ dosimetry results for three clinical trials with Bexxar therapy are shown. Values are expressed as the mean dose in centigrays (cgy). Liver

4 163 Bexxar for NHL Responding patients (%) n = 76 97% 63% Newly diagnosed n = 28 79% 50% Relapsed patient population n = 60 65% 17% Refractory Figure 3. Efficacy of Bexxar in various patient populations. Overall and complete response rates achieved with Bexxar therapy in different populations of patients with low-grade B-cell NHL. Reprinted with permission from Press [16]. median duration of 19.9 months [27]. Six patients remained in CR after a median of 50.8 months [29]. The high CR rate and long duration of CR in this trial encouraged further investigation. Multicenter Pivotal Trial A multicenter open-label trial was conducted in 60 patients with refractory low-grade or transformed low-grade NHL [12]. The patients were again heavily pretreated, with a median of four (range 2-13) prior chemotherapy regimens, and the median time from diagnosis was 53 months. Moreover, a large proportion of patients (38%) accrued to the study had transformed low-grade NHL. Patients in the trial had received at least two different chemotherapy treatments and had failed to respond to or had relapsed within 6 months after their LQC. Approximately half the patients had received a cyclophosphamide-containing regimen, and 15% had received single-agent fludarabine as their LQC. Following therapy with Bexxar, the OR rate was 65% (intent-to-treat), with a median duration of 6.5 months, and 20% of patients achieved CRs. Using McNemar s test to compare response rates and the log-rank test to compare response durations (Table 1), it was shown that the response rate and response duration achieved with Bexxar therapy were significantly greater than those achieved with the LQC (28% OR rate, 3% CR rate, and median response duration of 3.4 months) in this cohort. A univariate analysis of important prognostic variables demonstrated that histology, extent of prior therapy, prior radiotherapy, bone marrow involvement, and tumor burden were all significantly predictive of response [12]. Among patients with refractory low-grade NHL, 81% had ORs, compared with 39% of patients with transformed low-grade NHL. In addition, 90% of patients responded to therapy with Bexxar if they had received two or three prior therapies, versus 53% of patients who had received four or more prior therapies (p = 0.01). Bexxar therapy was also associated with a significant improvement in patient-assessed quality of life [30]. Qualityof-life data were collected for 72% of the patients participating in the multicenter pivotal trial at weeks 3, 7, 13, 19, 25, and 38, using the self-administered European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (+3), representing six functional scales and nine symptom scales. By week 19, the mean change from baseline indicated improvements for all scales except insomnia. In general, these improvements continued through week 38 and were comparable with scores reported by the general population. The authors reported statistically significant improvements in emotional and social functions, global health status, nausea and vomiting, and appetite loss at one or more time points. Furthermore, physical, role and social function, and global health status scores showed a >10-point mean change from baseline at week 38. Treatment of Rituximab Failures Therapy with Bexxar also has demonstrated safety and efficacy in patients who either failed to respond to rituximab or relapsed following treatment with rituximab. In a cohort of 40 patients with low-grade or transformed low-grade lymphoma, including 24 patients who failed to respond to rituximab, Bexxar therapy produced confirmed ORs in 68% of patients, with a median response duration of 14.7 months [31]. Moreover, 30% of patients had CRs, and the median duration of CR had not been reached. Multicenter Expanded-Access Study The efficacy of Bexxar therapy was further supported by a multicenter expanded-access study involving 65 academic Table 1. Response to Bexxar versus LQC in the pivotal trial (n = 60) Bexxar LQC p value a Response (%) <0.001 Median duration (months) <0.001 CR (%) 20 3 <0.001 Median duration (months) NR b 6.1 NA a McNemar s test for response, log-rank test for durations. b NR = not reached after 47 months. NA = not applicable. Data from Kaminski et al. [12].

5 Vose 164 and community sites in which the interim efficacy of Bexxar therapy in 475 patients with relapsed or refractory NHL enrolled in the study was recently assessed [28]. Of the 394 patients evaluable for response, 59% had ORs, with a median duration of 15 months, and 26% had CRs, with a median duration not reached after 9 months. The median time to progression for responders was 18 months. Treatment of Transformed Low-Grade NHL Transformation of low-grade lymphoma to a more aggressive histology is associated with poor survival (10- year survival rate of 13%) despite currently available treatment [32]. Therefore, the efficacy of Bexxar in transformed low-grade NHL is of particular interest. Data are available from 71 evaluable patients with transformed low-grade NHL who were treated with Bexxar in five trials [33]. That analysis included any patient with a biopsy consistent with histologic transformation at any time during the course of their disease and prior to study entry. For patients included in this analysis, the median time from diagnosis was 74 months (range months), the median time from transformation was 21 months (range months), and the median number of prior therapies was four (range 1-11). In addition, 28% of the patients had bulky disease and 57% had elevated lactate dehydrogenase (LDH) levels. Treatment with Bexxar resulted in an OR rate of 39%, with a median response duration of 20 months. In addition, 25% of patients had CRs, with a median duration of 36.5 months [33]. Based on these data, therapy with Bexxar appears to be effective in the treatment of transformed low-grade NHL and produces durable responses in this patient population. However, the transformed patients treated in this trial had a long duration between transformation and therapy with Bexxar and, therefore, the results may not be typical in all transformed NHL patients. Treatment of Patients with Poor Prognostic Features The efficacy of Bexxar therapy has also been evaluated in patients with poor prognostic factors, including elderly patients and patients with bulky disease. In a retrospective analysis, data were collected for 70 patients >60 years of age (median 69 years, range years) with low-grade (60%) or transformed low-grade (34%) NHL treated in phase I-III trials from [34]. In this cohort, 31% patients had bulky disease (>500 g). Treatment with Bexxar resulted in ORs in 60% of patients, with a median duration of 9 months, and 20% of patients had CRs, with a median duration not reached after a median of 15 months follow-up. A similar analysis of phase I-III clinical trials showed that therapy with Bexxar is efficacious in patients with a number of poor prognostic factors, including age >60 years, bulky disease, elevated LDH levels, and four or more prior chemotherapies (Table 2) [35]. Treatment of Newly Diagnosed Patients Seventy-six patients with newly diagnosed advancedstage follicular lymphoma were treated with Bexxar in a phase II single-institution study at the University of Michigan. Confirmed responses occurred in 72 patients (95%), and 56 patients (74%) achieved confirmed CRs [36]. Among patients with CRs, 45 remained in continuous complete remission from months, and the median duration of response and median progression-free survival had not been reached at a median follow-up of 43 months. At 5 years, 62% of patients remained free of progression. Treatment with Bexxar is also currently being investigated as first-line therapy in combination with fludarabine in newly diagnosed patients with NHL [37]. Of 35 patients treated, all achieved investigator-assessed responses, and 27 (77%) achieved CRs. The median duration of response had not been reached after a median follow-up of 23 months. The Southwest Oncology Group (SWOG) has also investigated the combination of Bexxar therapy with CHOP chemotherapy in newly diagnosed patients (trial S9911). Durability of Responses An analysis of the duration of responses to Bexxar therapy has demonstrated the excellent durability of CRs in 269 evaluable patients with low-grade or transformed low-grade NHL treated with Bexxar from , who have been Table 2. Rate and duration of OR and CR to therapy with Bexxar in patients with poor prognostic factors Prognostic factor OR rate (%) OR duration (months) CR rate (%) CR duration (months) Age >60 years NR Bulky disease (>500 g) prior chemotherapies Elevated LDH level NR = not reached Data from Rohatiner et al. [35].

6 165 Bexxar for NHL followed for a median of 1.5 years [38]. Within this population, 88 patients (33%) had CRs and 74 patients (28%) had confirmed CRs (i.e., two or more assessments 4 weeks apart). The median CR duration was 3.25 years; the median confirmed CR duration was 5 years. The median response duration had not been reached in newly diagnosed patients, and previously treated patients had median CR durations ranging from months. Safety Radioimmunotherapy with Bexxar in patients with low-grade and transformed low-grade NHL was shown to be safe and effective in five separate clinical trials and in a multicenter expanded-access study [14, 27, 28, 39-44]. All these trials used dosimetry to determine the patient-specific therapeutic dose required to administer the maximum tolerated TBD (75 cgy). Administration of a patient-specific therapeutic dose allows for greater uniformity of tumor dose with more predictable hematologic toxicities. This is critically important because total body residence times for the radiolabeled antibody can vary depending on tumor burden, bone marrow involvement, and the presence of splenomegaly. In all of these trials, therapy with Bexxar was well tolerated and hematologic toxicities were acceptable. As with the infusion of any foreign protein, treatment with Bexxar can be associated with infusion-related adverse events. The most common nonhematologic adverse events associated with Bexxar therapy are shown in Table 3 [43] and were typically mild to moderate in severity. In the multicenter, phase II trial, Bexxar infusions were well tolerated: 83% of patients had no infusion reactions, and there were no grade 3 infusion reactions reported [27]. Only 4% of infusions required a rate adjustment. In comparison, 33% of patients treated with rituximab required dose interruptions during the first infusion [1]. The dose-limiting toxicity associated with treatment with Bexxar is bone marrow suppression [27, 39]. Patients often develop mild-to-moderate, transient neutropenia, thrombocytopenia, or anemia, and the incidence of grade 3/4 hematologic toxicity is generally 30%-40% [45]. Nadirs typically occurred at weeks 4-6, with recovery of neutrophil and platelet counts to grade 2 by week 8-9. Among 677 patients with low-grade or transformed low-grade NHL who were treated with Bexxar, there were fairly low incidences of grade 4 neutropenia (16%), thrombocytopenia (3%), and anemia (2%) [45]. Median nadirs and times to nadir are shown in Table 4 [45]. Overall, 23% of patients required hematologic supportive care; 11% required platelet transfusions and 13% required red blood cell transfusions. Growth factor support, including filgrastim and erythropoietin, was Table 3. Summary of the most common nonhematologic toxicities in patients with low-grade or transformed low-grade NHL treated with Bexxar in the expanded-access study (n = 359) a Grade (%) Adverse event 1/2 3/4 Asthenia 20 <3 Nausea 17 <1 Fever 11 <2 Pain 9 <2 Rash 9 <0 Chills 8 <1 Headache 7 <1 Arthralgia 6 <1 Vomiting 6 <1 Diarrhea 6 <1 Myalgia 6 <1 Pruritus 6 <0 Increased cough 6 <0 a Events occurring in >5% of patients; all reported events. Data from Schenkein et al. [43]. required by 15% of patients. As might be expected, hematologic toxicities were proportional to the extent of prior therapy. None of the previously untreated patients experienced grade 4 thrombocytopenia or anemia, and only 5% experienced grade 4 neutropenia. Furthermore, none of the previously untreated patients required supportive care. The hematologic toxicities associated with Bexxar therapy have not been shown to correlate with the extent of bone marrow involvement [46]. Among patients with 20%-25% bone marrow involvement, 50% had grade 4 neutropenia, and there was no grade 4 thrombocytopenia or anemia. In a retrospective analysis of elderly patients (>60 years of age), safety data were collected on 70 patients with lowgrade (60%) or transformed low-grade (34%) NHL treated in phase I-III trials from (Table 5) [34]. The median age was 69 years (range years), and 31% of patients had bulky disease (>500 g). Safety in this subgroup of patients was comparable with that in patients <60 years of age. Subsequently, safety data were assessed in 269 patients >60 years of age with low-grade (72%) or transformed lowgrade (28%) NHL enrolled in multiple clinical trials, including the expanded-access study, from [44]. This analysis, in a larger patient population, demonstrated that therapy with Bexxar was generally well tolerated in elderly patients. Grade 4 neutropenia occurred in 16% of patients, and grade 4 thrombocytopenia occurred in 2% of patients. Only 3% of dosimetric and therapeutic infusions required

7 Vose 166 Table 4. Summary of hematologic toxicities in patients with lowgrade or transformed low-grade NHL treated with Bexxar Platelets Median nadir 66,000/mm 3 Median time to nadir 33 days Nadir <10,000/mm 3 3% Neutrophils Median nadir 1,200 cells/mm 3 Median time to nadir 42 days Nadir <500 cells/mm 3 17% Hemoglobin Median nadir 11 g/dl Median time to nadir 43 days Nadir <6.5 g/dl 2% Data from Kaminski et al. [45]. rate adjustments. These data suggest that specific agerelated dose adjustments are not required for Bexxar therapy. Potential long-term safety concerns include damage to the thyroid, development of human antimouse antibodies (HAMAs), and secondary malignancies. All patients are treated with a thyroid-blocking agent to prevent the development of hypothyroidism. Elevated thyroid-stimulating hormone (TSH) levels were observed in five patients (8.5%) in the phase I study, and two of those patients were placed on thyroid hormone supplementation [27]. In the multicenter expanded-access study, TSH elevation occurred in 3% of patients treated with Bexxar therapy [28]. The percent of patients who develop HAMAs is related to the extent of prior therapy and has ranged from 0%-8% in previously treated patients [27, 28], whereas 63% of previously untreated patients developed a HAMA response [36]. Although patients treated with Bexxar may develop HAMAs, the immune response to tositumomab does not appear to have marked clinical consequences. Hematologic and nonhematologic secondary malignancies are of concern with any radiation-based therapy. To date, at a median follow-up of 1.5 years (range years) from the dosimetric dose, secondary myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) has been reported in 19 (3.1%) of 620 heavily pretreated patients who received therapy with Bexxar [47]. Those patients had received a median of three prior therapies, and the median time from diagnosis to study entry was 45 months. This observed incidence of secondary MDS/AML following Bexxar therapy is consistent with the reported cumulative incidence in lymphoma patients Table 5. Summary of adverse events a and hematologic toxicities in patients >60 years of age with NHL treated with Bexxar Patients (%) Adverse event n = 70 Fever 41 Asthenia 36 Nausea 31 Anorexia 20 Diarrhea 20 Pain 19 Increased cough 19 Rash 16 Chills 16 Neutrophils Median nadir 1,200/mm 3 Median time to nadir 41 days Nadir <500/mm 3 19% Platelets Median nadir 65,000 cells/mm 3 Median time to nadir 33 days Nadir <10,000/mm 3 4% a Reported in >11% of patients. Data from Gregory et al. [34]. 5-6 years after initial cytotoxic therapy [48]. A retrospective review of baseline bone marrow biopsies showed that five of those patients had evidence of MDS/AML at study entry, and chromosomal analysis at clinical diagnosis of MDS/AML revealed changes in chromosomes 5 and/or 7 consistent with alkylator-induced chromosomal damage in 11 of 12 patients tested. Moreover, none of the 76 newly diagnosed patients who were treated with Bexxar had developed MDS/AML at a median follow-up of 4.1 years (range years) [47]. While longer follow-up is needed to determine the potential contribution of treatment with Bexxar to the development of MDS/AML, none of the available data from multiple studies demonstrate that therapy with Bexxar substantially increased the risk above what would be expected in a group of heavily pretreated lymphoma patients. Dosing and Administration The complete course of therapy with Bexxar is carried out in two phases. First, patients receive a trace-labeled dosimetric dose, and dosimetry studies are conducted to establish the patient-specific therapeutic dose. Second, a single therapeutic dose is administered. With appropriate instructions, the patient can generally be treated on an outpatient basis.

8 167 Bexxar for NHL Patient-Specific Dosing The administered dose of Bexxar is calculated based on patient-specific variables. Dosimetry ensures that each patient receives the maximum tolerated TBD, which should maximize therapeutic benefit and ensure that organ toxicity is minimal. The delivered therapeutic dose is determined based on the clearance rate of the radiolabeled antibody from each individual patient (i.e., patient-specific residence time), which is affected primarily by the patient s lean body mass and tumor burden [49]. Patients first receive an infusion of unlabeled antibody followed by a trace-labeled dosimetric dose of antibody, and total-body gamma camera counts are then obtained at three times over the next 6-7 days. The therapeutic dose is then calculated based on the effective half-life of the antibody to ensure that the patient receives a dose calculated to deliver a 75-cGy TBD (for patients with baseline platelet counts 150,000/mm 3 ). Patients who have platelet counts of 100, ,999/mm 3 receive TBDs of 65 cgy; Bexxar therapy is not recommended for patients with platelet counts below 100,000/mm 3. The actual amount of radioactivity administered to each patient is variable (ranging from mci), with a median of 81.8 mci [45]. Details of the Bexxar regimen are illustrated in Figure 4 [50]. Oral iodine supplements to block I-131 uptake by the thyroid gland are administered beginning 1 day before administering the dosimetric infusion and continuing for 2 weeks after the therapeutic dose. Patients are also pretreated with oral acetaminophen (650 mg) and either diphenhydramine (50 mg) or chlorpheniramine (4 mg) 1 hour before each infusion of tositumomab to reduce infusion reactions to the antibody. A 60-minute infusion of 450 mg unlabeled (i.e., cold) tositumomab is administered before administering the dosimetric dose on day 0 to improve biodistribution of the radiolabeled antibody. The dosimetric dose of iodine I 131- labeled tositumomab (5 mci) is then administered via a 20- minute infusion followed by a 10-minute flush. The patient then undergoes three whole-body gamma camera counts (immediately postinfusion on day 0; on day 2, 3, or 4; and on day 6 or 7). Based on the calculated residence time of the antibody, a patient-specific therapeutic dose is calculated. From days 7-14, the patient receives a 60-minute infusion of 450 mg cold tositumomab followed by the therapeutic dose of iodine I 131 tositumomab via a 20-minute infusion plus a 10- minute flush. Dosage adjustments are made for patients with low platelet counts (100, ,999/mm 3 ) and for obese patients (>135% of ideal body weight). Administration in an Outpatient Oncology Clinic At many institutions, the administration of Bexxar is handled by a dedicated treatment team and is carried out entirely in an outpatient oncology clinic. This approach was pio- Dosimetric dose day 0 Therapeutic dose between days 7-14 Cold dose 450 mg unlabeled anti-b1 antibody Office/hospital Outpatient Hot dose 5 mci I-131 tostitumomab (35 mg) Office/approved facility Outpatient Whole body counts Day 0 Day 2, 3, or 4 Day 6 or 7 Cold dose 450 mg unlabeled anti-b1 antibody Office/hospital Outpatient Hot dose x mci I-131 tostitumomab (35 mg) to deliver 75-cGy total body dose Office/approved facility Outpatient Figure 4. Treatment regimen for therapy with Bexxar. X = patient-specific dose. Reprinted with permission from Hohenstein et al. [50].

9 Vose 168 neered by investigators at the University of Nebraska Medical Center (UNMC) (Omaha, NE) and the Hoag Cancer Center (Newport Beach, CA) [50, 51]. The UNMC treatment team is composed of hematology/oncology and nuclear medicine personnel who ensure the safe delivery of Bexxar and are responsible for providing clear and comprehensive patient education to maintain the safety of caregivers and family members when the patient is released. Members of the UNMC treatment team have various responsibilities [50]: The hematologist/oncologist is responsible for identifying appropriate patients for treatment with Bexxar (i.e., patients with relapsed or refractory low-grade or transformed low-grade B-cell NHL), prescribing the SSKI supplement, monitoring the patient while in the hospital and performing the follow-up to determine response to treatment, and managing adverse events. The nuclear medicine physician or radiation oncologist is primarily responsible for prescribing and directly supervising the administration of Bexxar and overseeing the calculations to determine the patient-specific therapeutic dose. After administering the therapeutic dose, the nuclear medicine physician, radiation safety officer, or radiation oncologist is responsible for determining whether the patient can be released and for providing the patient with necessary radiation safety precautions. The nuclear pharmacist, who is onsite at the UNMC, is responsible for ordering, preparing, and administering both the cold Bexxar infusions. The nuclear medicine technologist is responsible for performing whole-body gamma camera scans and ensuring the accuracy of the dosimetric data used to calculate the therapeutic dose. The oncology nurse assists the nuclear pharmacist, monitors the patient during infusions, and treats any infusion-related reactions. The oncology or radiology nurse coordinator has the primary responsibility for initial patient screening, ordering pharmaceuticals, and scheduling treatment, including gamma camera scans. The nurse coordinator is also responsible for patient education. The radiation safety officer is responsible for monitoring all iodine I 131 tositumomab infusions for safety and patient radiation levels during and after treatment. General Radiation Safety Bexxar can be safely administered in an outpatient oncology clinic, although patients are required to have access to a nuclear medicine facility equipped to perform standard whole-body gamma camera counts. The radiation safety precautions followed during the administration of Bexxar are similar to those followed during standard radioiodine therapy; however, because the I-131 is conjugated to an antibody, the problems associated with the volatility of sodium iodide are minimized. It is recommended that the infusion equipment be dedicated exclusively to administering Bexxar; however, under normal operating conditions, infusion pumps should not become contaminated. During the infusion, the iodine I 131 tositumomab is shielded, patients are usually isolated in a specially prepared room, and access to the room is restricted. Patients can generally be released immediately after the infusion, as described below. Patient Release Guidelines The release of patients administered Bexxar must be carried out in compliance with federal and state regulations. In states that have adopted the Nuclear Regulatory Commission (NRC) regulations, patient release is carried out in compliance with NRC regulations specified in the Code of Federal Regulations 10 CFR Part 35 and Regulatory Guide 8.39, Release of Patients Administered Radioactive Materials [52]. This regulatory guide provides specific guidelines that must be followed for determining when a patient can be released from the hospital. These new regulations specify that patients can be released as long as the radiation doses to other individuals (e.g., family members) are not likely to exceed 500 millirems (mrem). Determining Patient-Specific Release Criteria Patient-specific release criteria that are consistent with federal regulations have been developed based on the total body residence time of the antibody (which is determined by serial gamma camera scans after administering the dosimetric dose) and the measured dose rate at 1 m in mrem/hour (measured immediately after administering the therapeutic dose). With this information, a simple look-up table is consulted to determine if the patient can be released. Most patients can be released immediately after administering the therapeutic dose. A recent study estimated the radiation exposure of family members based on an analysis of 139 patients treated with Bexxar [53]. The mean activity administered to these patients was 84 mci (range mci), and the mean observed dose rate at 1 m was 10.9 mrem/hour (range 4-24 mrem/hour). The estimated radiation exposure to maximally exposed family

10 169 Bexxar for NHL members and caregivers ranged from mrem. This study suggested that all 139 patients qualified for immediate release after Bexxar therapy. Patient-Release Instructions Once it has been determined that a patient can be released, NRC regulations state that the patient must be provided with clear, written instructions. An example of such patient instructions is shown in Figure 5 [54]. These instructions advise patients on how close they can be to others and how they should conduct themselves and dispose of bodily wastes to minimize radiation exposure to others. For example, patients are instructed to sleep in a separate bed ( 6 feet from others), not to take a long trip ( 4 hours) during which they will be sitting near others, to maintain a safe distance ( 6 feet) from others, and to avoid contact with children and pregnant women. The duration of these restrictions is calculated on each individual patient s residence time and dose rate at 1 m. For example, a patient with a residence time of 75 hours and a dose rate of 10 mrem/hour would be restricted to sleeping in a separate bed for 6 days, not taking long trips for 1 day, and maintaining safe distances from children and pregnant women for 9 days. When a patient has demonstrated an understanding of these restrictions and appears capable of complying based on an interview, that patient can be released. Effectiveness of Release Guidelines These patient release instructions were validated by providing radiation-monitoring devices to caregiving family members of 22 patients who were treated with Bexxar and released [55]. Radiation exposure levels were monitored for 2-17 days after the therapeutic dose administration, which ranged from mci in these patients. The radiation exposure to caregivers ranged from mrem, with an average exposure of 144 mrem. This was Patient identifier: well below the 500-mrem limit set by the NRC. These results indicate that patients treated with Bexxar can be released with confidence that the instructions they are provided are adequate and that the exposure of caregivers and family members is not likely to exceed 500 mrem. CONCLUSIONS Radioimmunotherapy with Bexxar has been shown to be safe and effective for the treatment of indolent lymphoma. The advantage of Bexxar over conventional radiotherapy, chemotherapy, and unconjugated antibodies is the ability to target a patient-specific dose of radiation to the tumor with Instructions to the released patient Activity administered (A): mci Measured dose rate: Administration date: For you to leave the hospital as an outpatient you must follow these precautionary measures: Instruction 1. Sleep in a separate bed (at least 6 feet separation) 2. Do not take a long trip (4 hours or more) sitting near others (e.g., car, train, airplane, bus) 3. Other instructions In addition, while following the above instructions, you must: Maintain a distance of at least 6 feet from others whenever possible Avoid contact with pregnant women and children When taking shorter trips during the period of restricted travel, sit as far as possible from others Have the sole use of a bathroom if possible Sit while urinating and flush the toilet twice with the lid down Wash hands frequently including after each toilet use and shower daily Drink plenty of liquids Keep dishes and utensils separated for 1 week and wash separately Use separate towels, wash cloths, and toothbrush from rest of household Hold clothing and linen (sheets and towels) for 1 week before laundering and launder separately from rest of household's laundry Avoid using disposable items that cannot be flushed down the toilet Show these instructions to any physician or other healthcare provider visited Signatures: Physician: Radiation safety officer: Patient/guardian: Figure 5. Instructions for releasing a patient treated with Bexxar [54]. mrem/h at 1 meter Duration, days Date: Date: Date:

11 Vose 170 minimal toxicity to normal organs. Clinical trials have demonstrated that treatment with Bexxar induces high overall and CR rates and durable complete remissions in relapsed and refractory patients, newly diagnosed patients, and patients who failed rituximab. In relapsed and refractory patients, Bexxar produced superior response rates and durations when compared with patients LQC and improved quality of life, thus providing a viable treatment option for patients who have become refractory to chemotherapy. Hematologic toxicities were generally short term, predictable, and manageable. It has also been demonstrated that Bexxar can be administered safely in the outpatient setting by following established and validated guidelines. FUTURE DIRECTIONS Given the proven efficacy of therapy with Bexxar in patients with relapsed and refractory low-grade NHL, it may play an important role as second-line therapy in patients who have failed prior chemotherapy, rituximab, or both. High response rates and durable responses have also been demonstrated in patients with transformed low-grade NHL, suggesting that Bexxar could potentially be effective in the treatment of aggressive lymphoma. Its role as first-line therapy for indolent lymphoma has yet to be defined. However, several cooperative group trials are investigating therapy with Bexxar in combination with chemotherapy in newly diagnosed patients. Based on the encouraging results of the SWOG trial S9911, an intergroup trial has been initiated to compare CHOP plus rituximab with CHOP plus Bexxar for follicular lymphoma. A myeloablative I-131-tositumomab regimen with stem-cell support is also being actively investigated and appears promising. In this setting, RIT has advantages over total-body irradiation and is less toxic than many preparative chemotherapy regimens. The role of RIT for the treatment of indolent lymphoma will undoubtedly continue to evolve. REFERENCES 1 McLaughlin P, Grillo-Lopez AJ, Link BK et al. Rituximab chimeric anti-cd20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998;16: Hekman A, Honselaar A, Vuist WM et al. Initial experience with treatment of human B cell lymphoma with anti-cd19 monoclonal antibody. Cancer Immunol Immunother 1991;32: Juweid M, Sharkey RM, Markowitz A et al. Treatment of non- Hodgkin s lymphoma with radiolabeled murine, chimeric, or humanized LL2, an anti-cd22 monoclonal antibody. Cancer Res 1995;55(suppl):5899s-5907s. 4 Dyer MJ, Hale G, Hayhoe FG et al. Effects of CAMPATH-1 antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype. Blood 1989;73: Hu E, Epstein AL, Naeve GS et al. A phase Ia clinical trial of LYM-1 monoclonal antibody serotherapy in patients with refractory B cell malignancies. Hematol Oncol 1989;7: Link BK, Wang H, Byrd JC et al. Phase I trial of humanized 1D10 (Hu1D10) monoclonal antibody targeting class II molecules in patients with relapsed lymphoma. Proc Am Soc Clin Oncol 2000;19:24a. 7 Shan D, Ledbetter JA, Press OW. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood 1998;91: Buchsbaum DJ, Wahl RL, Normolle DP et al. Therapy with unlabeled and 131I-labeled pan-b-cell monoclonal antibodies in nude mice bearing Raji Burkitt s lymphoma xenografts. Cancer Res 1992;52: Flieger D, Renoth S, Beier I et al. Mechanism of cytotoxicity induced by chimeric mouse human monoclonal antibody IDEC-C2B8 in CD20-expressing lymphoma cell lines. Cell Immunol 2000;204: Golay J, Zaffaroni L, Vaccari T et al. Biologic response of B lymphoma cells to anti-cd20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 2000;95: Czuczman MS, Grillo-Lopez AJ, White CA et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-cd20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17: Kaminski MS, Zelenetz AD, Press OW et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-hodgkin s lymphomas. J Clin Oncol 2001;19: Kaminski MS, Estes J, Tuck M et al. Iodine I 131 tositumomab therapy for previously untreated follicular lymphoma (FL). Proc Am Soc Clin Oncol 2000;19:5a. 14 Kaminski MS, Estes J, Zasadny KR et al. Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-hodgkin lymphoma: updated results and long-term followup of the University of Michigan experience. Blood 2000;96: Wiseman GA, White CA, Sparks RB et al. Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low- grade, follicular, or transformed B-cell non-hodgkin s lymphoma. 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12 171 Bexxar for NHL 19 Sharkey RM, Motta-Hennessy C, Pawlyk D et al. Biodistribution and radiation dose estimates for yttrium- and iodine-labeled monoclonal antibody IgG and fragments in nude mice bearing human colonic tumor xenografts. Cancer Res 1990;50: Press OW, Appelbaum FR, Eary JF et al. Radiolabeled antibody therapy of lymphomas. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important Advances in Oncology. Philadelphia: JB Lippincott Co, 1995: Colcher D. Centralized radiolabeling of antibodies for radioimmunotherapy. J Nucl Med 1998;39(suppl):11S-13S. 22 Press OW, Farr AG, Borroz KI et al. Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies. Cancer Res 1989;49: Press OW, Howell-Clark J, Anderson S et al. Retention of B- cell-specific monoclonal antibodies by human lymphoma cells. Blood 1994;83: Press OW, Shan D, Howell-Clark J et al. Comparative metabolism and retention of iodine-125, yttrium-90, and indium- 111 radioimmunoconjugates by cancer cells. Cancer Res 1996;56: DeNardo GL, Kukis DL, Shen S et al. 67Cu- versus 131Ilabeled Lym-1 antibody: comparative pharmacokinetics and dosimetry in patients with non-hodgkin s lymphoma. Clin Cancer Res 1999;5: Kaminski MS, Zasadny KR, Francis IR et al. Iodine-131-anti- B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 1996;14: Vose JM, Wahl RL, Saleh M et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-hodgkin s lymphomas. J Clin Oncol 2000;18: Leonard JP, Frenette G, Dillman RO et al. Interim safety and efficacy results of Bexxar in a large multicenter expanded access study. Blood 2001;98:133a. 29 Leonard JP, Zelenetz AD, Vose JM et al. Bexxar (tositumomab and iodine I 131 tositumomab) results in durable long-term responses in patients with poor prognosis, multiple relapsed (Rel) and refractory (Ref) low-grade or transformed low-grade non-hodgkins Lymphoma (NHL). Blood 2001;98:683a. 30 Kaminski MS, Kauf TL, Zelenetz AD et al. Treatment of transformed and refractory low-grade lymphoma with Bexxar therapy is associated with improvements in quality of life. Blood 2001;98:427a. 31 Horning SJ, Younes A, Lucas J et al. Rituximab treatment failures: tositumomab and iodine I 131 tositumomab [Bexxar ] can produce meaningful durable responses. Blood 2002;98(suppl):357a. 32 Ersboll J, Schultz HB, Pedersen-Bjergaard J et al. Follicular lowgrade non-hodgkin s lymphoma: long-term outcome with or without tumor progression. Eur J Haematol 1989;42: Kaminski MS, Zelenetz AD, Leonard J et al. Bexxar radioimmunotherapy produces a substantial number of durable complete responses in patients with multiply relapsed or refractory low grade or transformed low grade non-hodgkin s lymphoma. Blood 2002;100:356a. 34 Gregory SA, Zelenetz A, Knox S et al. Bexxar is an effective and well tolerated therapy in elderly patients with non-hodgkin lymphoma (NHL). Proc Am Soc Clin Oncol 2001;20:285a. 35 Rohatiner A, Kaminski M, Leonard J et al. Bexxar radio immunotherapy is efficacious in non Hodgkin s lymphoma (NHL) patients with poor prognostic features. Proc Am Soc Clin Oncol 2001;20:286a. 36 Kaminski MS, Tuck M, Regan D et al. High response rates and durable remissions in patients with previously untreated, advanced-stage, follicular lymphoma treated with tositumomab and iodine I-131 tositumomab (Bexxar ). Blood 2002;100: Leonard JP, Coleman M, Kostakoglu L et al. Triple modality therapy for follicular low-grade lymphoma: initial treatment with fludarabine followed by Bexxar (tositumomab and iodine I 131 tositumomab). Blood 2001;96:844a. 38 Leonard JP, Zelenetz AD, Vose JM et al. Iodine I 131 tositumomab for patients with low-grade or transformed low-grade NHL: complete response data. Blood 2000;96:728A. 39 Kaminski MS, Zelenetz AD, Press O et al. Multicenter, phase III study of iodine-131 tositumomab (anti-b1 antibody) for chemotherapy-refractory low-grade or transformed low-grade non-hodgkin s lymphoma (NHL). Blood 1998;92(suppl 1):316a. 40 Knox SJ, Goris ML, Davis TA et al. Randomized controlled study of 131I anti-b1 versus unlabeled-anti-b1 monoclonal antibody in patients with chemotherapy refractory low-grade non-hodgkin s lymphoma. J Radiat Oncol Biol Phys 1997;39(suppl): Kaminski MS, Gribbin T, Estes J et al. I-131 anti-b1 antibody for previously untreated follicular lymphoma (FL): clinical and molecular remissions. Proc Am Soc Clin Oncol 1998;17:2a. 42 Kaminski MS. Tolerance of treatment subsequent to frontline Bexxar (tositumomab and iodine I-131 tositumomab) in patients (pts) with follicular lymphoma. Blood 2001;98:603a. 43 Schenkein DP, Leonard J, Harwood S et al. Interim safety results of Bexxar in a large multicenter expanded access study. Proc Am Soc Clin Oncol 2001;20:285a. 44 Gregory SA, Coleman M, Dillman RO et al. Bexxar is a well-tolerated therapy in elderly patients with low-grade or transformed low-grade non-hodgkin s lymphoma (NHL). Blood 2001;98:605a. 45 Kaminski MS, Gregory SA, Fehrenbacher L et al. Acute and delayed hematologic toxicities associated with Bexxar therapy are modest: overall experience in patients with low-grade and transformed low-grade NHL. Blood 2001;98:339a. 46 Gregory SA, Leonard J, Coleman M et al. Relationship of degree of bone marrow involvement with hematologic toxicity in patients with non-hodgkin s lymphoma treated with tositumomab and iodine I 131 tositumomab therapy. Presented at the 39th American Society of Clinical Oncology annual meeting, Chicago, IL, May 31-June 2.

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